We have observed that normal volunteers, when made acidotic and exposed to hypoxia had much reduced production of erythropoietin as compared with these same volunteers during a control period. This was thought to result from blocking (due to acidosis) of the initial shift in the oxygen dissociation curve to the left which results from respiratory alkalosis. The latter normally leads to increased oxygen affinity and hence increased tissue hypoxia, thus favoring further erythropoietin production. Acidosis by averting the shift in the oxygen curve results in a relative decrease in tissue hypoxia and the stimulus to erythropoietin production. In the current research proposal, we plan to further evaluate changes in oxygen delivery resulting from changes in pH and intraerythrocytic metabolism and their effect on erythropoietin production and erythropoiesis in clinical and experimental situations where changes in red cell production are known to occur but are incompletely understood. We propose to dissect out the various effects by using hyperventilation, NaHCO3 and cyanate in experimental animals and further to evaluate erythropoietin production in ureter ligated and nephrectomized animals and in starved animals, the effect of testosterone, and genetic differences in the response of animals to hypoxia. Clinically, we propose to evaluate erythropoietin production and the development of polycythemia in patients with chronic obstructive lung disease (bronchitis-emphysema).